Revised diagnostic criteria seek to avoid over-diagnosis of Alzheimer’s disease

The diagnosis of Alzheimer’s disease (AD) is currently largely based on the presence of biomarkers. This can lead to problematic overdiagnosis if misinterpreted.

To combat this problem, a global panel of experts led by Hôpitaux Universités de Genève (HUG), the University of Geneva and the Salpêtrière Hospital have drawn up recommendations. Based on a review of the scientific literature, they argue that both clinical symptoms and biomarkers should be taken into account. This new approach avoids the diagnosis of AD in people with abnormal biomarkers who will never develop memory impairment and provides a monitoring process tailored to each individual. These recommendations were published in the Journal of the American Medical Association – Neurology (JAMA Neurology).

According to the Association Alzheimer Suisse, by 2050 the number of people in Switzerland affected by Alzheimer’s disease and other forms of dementia will exceed 300,000, which is twice as many as today.

To facilitate research into this disease, a group of scientists in the United States defined new, very broad diagnostic criteria three months ago. For them, an AD diagnosis would be defined by the mere presence of biomarkers, such as amyloid β and tau protein, without taking into account memory function and other cognitive functions. These biomarkers are quantifiable in cerebrospinal fluid, on PET brain images or in blood and have been associated with the brain degeneration that gives rise to AD.

For the global expert panel led by Prof. Giovanni Frisoni, Head of the Memory Center at the HUG and Professor, Department of Readaptation and Geriatrics at the UNIGE Faculty of Medicine, and Professor Bruno Dubois, Professor of Neurology at Sorbonne University and Head of the Department in the Salpêtrière Hospital in Paris, the impact of these new criteria will be that countless perfectly healthy people will be diagnosed with AD based solely on a laboratory test, while never developing memory disorders. So they formed a panel of experts to make new recommendations.

A clinical and biological definition

According to professors Frisoni, Dubois and their colleagues, biomarkers are only useful if they are accompanied by a multidisciplinary medical consultation and memory tests. These tests can reveal short-term memory problems, namely the inability to remember recent information. People affected may also lose their points of reference and become disoriented. They will often have difficulty speaking, finding their words or their reasoning will become less clear. Finally, behavioral changes such as irritability, anxiety, depression and social isolation sometimes occur.

This diagnostic nuance is crucial for individuals who have positive biomarkers but do not show clinical symptoms. If these represent only 3% in the 50 to 59 age category, this figure rises to 40% in the 80 to 89 age category. Based on the American Alzheimer’s Association criteria, all of these people would qualify for an AD diagnosis. However, according to Professor Frisoni, “70% of all these people will never develop AD.” Why would you give them this harrowing diagnosis?”

New categories

The international team’s recommendation amounts to rethinking biomarkers not as equivalents of AD, but simply as indicators of the deposition of toxic proteins that go hand in hand with the disease. This nuance allows defining two categories of individuals with abnormal biomarkers: those with abnormal memory tests and those with normal tests. The first group has AD, while the second group only has an increased risk of developing AD, but does not yet have it. They are therefore not considered sick, but rather at risk.

A new patient journey in Geneva

Within the clinical context, these categories allow the development of new monitoring strategies for people at risk who are not currently treated. Changes in best practices have already been initiated in Geneva. “We have received four years of funding from the State of Geneva so that our Memory Center can provide a new patient pathway for people at risk in early 2025. These trips will also specifically include an evaluation of all known risk factors, including biomarkers, as well as depression and social isolation.”

Future research challenges

The formulation of these two categories of individuals is also important for research as it allows for the creation of better stratified longitudinal cohorts. “The weight of each risk factor is currently quite imprecise, Professor Frisoni clarifies, and the addition of these categories to longitudinal studies will allow us to quantify the weight of each factor much more accurately.”

The inclusion of asymptomatic individuals in clinical trials will also make it possible to test the effectiveness of treatments, including amyloid-lowering agents, that attempt to reduce the risk of developing AD and associated cognitive impairment. “In the long term, we envision personalized treatments, based on lifestyle and nutritional principles such as probiotics, but also on anti-amyloid medications, tailored to the risk profile of the individual,” concludes Prof. Frisoni.